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Related Experiment Videos

Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level.

J Han1, T Brown, B Beutler

  • 1Howard Hughes Medical Institute, University of Texas, Dallas 75235.

The Journal of Experimental Medicine
|February 1, 1990
PubMed
Summary

Bacterial endotoxin enhances cachectin/tumor necrosis factor (TNF) production by increasing translational efficiency, not mRNA levels. This response involves the 3'-untranslated TTATTTAT element and flanking sequences, leading to significant CAT synthesis induction.

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Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Cachectin/TNF biosynthesis is primarily regulated post-transcriptionally.
  • Bacterial endotoxin induces cachectin/TNF production by altering macrophage cytoplasmic conditions.
  • The 3 -untranslated TTATTTAT element can repress mRNA translation.

Purpose of the Study:

  • To investigate the role of cachectin/TNF 3 -untranslated regions in endotoxin-induced gene expression.
  • To determine if downstream sequences mediate translational enhancement in response to endotoxin.

Main Methods:

  • Constructs with CAT coding sequence and cachectin/TNF 3 -untranslated regions were used.
  • CAT synthesis and activity were measured following endotoxin activation.
  • Changes in cytoplasmic mRNA concentration and translational efficiency were assessed.

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Main Results:

  • Downstream sequences in cachectin/TNF mRNA mediated over 200-fold induction of CAT synthesis upon endotoxin activation.
  • Induction was due to enhanced translational efficiency, not increased mRNA levels.
  • The TTATTTAT element and flanking sequences were crucial for this endotoxin response.

Conclusions:

  • Endotoxin-induced cachectin/TNF production involves post-transcriptional regulation via translational enhancement.
  • The 3 -untranslated region, particularly the TTATTTAT element, plays a key role in this derepression mechanism.